INTRODUCTION — Gaucher disease (GD) is an inborn error of metabolism that affects the recycling of cellular glycolipids. It results from deficiency of a lysosomal enzyme glucocerebrosidase EC126.96.36.199 (also known as glucosylceramidase or acid beta-glucosidase [GBA]). Glucosylceramide (also called glucocerebroside) and several related compounds that ordinarily are degraded to glucose and lipid components by glucocerebrosidase accumulate within the lysosomes of cells in patients with GD .
Treatment of GD is tailored to the individual patient because of the variability in the manifestations, severity, progression of the disease, and treatment response [2,3]. GD was the first inherited metabolic disorder for which enzyme replacement therapy (ERT) became available [4,5]. Additional therapies include substrate reduction therapy (SRT) and supportive care measures to manage associated conditions. Investigations are continuing into alternate treatment strategies, including gene therapy and molecular chaperones.
The treatment of GD is discussed here. The pathogenesis, genetics, clinical manifestations, diagnosis, initial assessment, and routine monitoring are discussed separately. (See "Gaucher disease: Pathogenesis, clinical manifestations, and diagnosis" and "Gaucher disease: Initial assessment, monitoring, and prognosis".)
THERAPEUTIC GOALS — The basic goals of treatment are elimination or improvement of symptoms, prevention of irreversible complications, and improvement in the overall health and quality of life [6-9]. An additional goal in children is optimization of growth. An international panel of clinicians with extensive clinical experience in GD developed a list of therapeutic goals for use as guides for optimal treatment (table 1 and table 2 and table 3). Regular monitoring is performed to assess the response to therapy, make adjustments when goals are not met, and ensure the maintenance of achieved goals (table 4). The frequency of reevaluation depends upon disease severity and should be assessed on an individual basis . (See "Gaucher disease: Initial assessment, monitoring, and prognosis".)
Visceral, hematologic, skeletal, and other aspects of nonneuronopathic disease are considered separately since each of these components is relatively independent of the others with respect to disease burden and response to therapy . Skeletal manifestations are associated with the greatest morbidity and, once present, are among the least responsive to Gaucher-specific therapy. Enzyme replacement therapy (ERT) or substrate reduction therapy (SRT) may slow or prevent progression of skeletal complications, but osteonecrosis, osteosclerosis, and vertebral compression are irreversible. Early treatment may prevent or lessen the severity of these complications, and therefore, early identification is crucial to improving ultimate outcome [11,12]. (See "Gaucher disease: Pathogenesis, clinical manifestations, and diagnosis".)
ENZYME REPLACEMENT THERAPY — The decision to offer Gaucher-specific therapy (enzyme replacement therapy [ERT] or substrate reduction therapy [SRT]) in patients with nonneuronopathic GD (type 1 Gaucher disease [GD1]) is based upon disease burden, as determined by the initial assessment, or significant disease progression, as demonstrated through regular follow-up. ERT with a recombinant glucocerebrosidase (imiglucerase, velaglucerase alfa, or taliglucerase alpha; the last is not approved for use in the European Union) or SRT with eliglustat (approved only for adults) are the preferred treatments for patients with clinically significant manifestations of nonneuronopathic GD (GD1). ERT with imiglucerase or velaglucerase (off-label use) is also an option in patients with chronic neuronopathic GD (type 3 [GD3]) who have visceral manifestations and in patients who are suspected to have GD3 based upon genotype or family history, but it does not prevent or reverse central nervous system (CNS) involvement (table 5) [6,13-19]. (See 'Substrate reduction therapy' below.)
Clinical trials conducted in the late 1980s and early 1990s demonstrated the efficacy of ERT in patients with GD1 who were treated with glucocerebrosidase prepared from human placenta [20,21]. A recombinant preparation has been available since 1993. (See 'Preparation' below.)
Indications — Published guidelines for ERT treatment in children and adults with GD were developed by consensus of international experts, using data from the International Collaborative Gaucher Group (ICGG) Gaucher Registry and local experience [6,10,12,14,22].
ERT with imiglucerase, velaglucerase, or taliglucerase according to local approvals (taliglucerase is not approved in the European Union) is indicated for the following patients with nonneuronopathic (GD1) disease [12,23,24]:
●Symptomatic children (including those with organomegaly, anemia, malnutrition, growth retardation, impaired development, and/or fatigue) [7,24] since early presentation is associated with more severe disease .
●Adult patients with symptomatic disease (eg, anemia, thrombocytopenia <60,000/microL, liver >2.5 times normal size, spleen >15 times normal size, radiologic or clinical evidence of skeletal disease). The exact starting criteria vary according to local guidelines and numeric values (eg, normal range for platelet counts) and should always be considered in the context of clinical impact on the patient.
The European Working Group on Gaucher Disease has formulated consensus guidelines for the treatment of neuronopathic GD [25,26]. These recommendations are summarized in the table (table 5). In brief, ERT should be considered for patients with GD3 disease with visceral manifestations [23,27]. In addition, it should be offered in patients suspected to have GD3  based upon genotype or family history, even before the onset of neurologic signs or symptoms. ERT may also have palliative effects on visceral manifestations in GD2 disease, but it does not alter the fatal neurologic outcome [26,28-30].
Preparation — Imiglucerase is produced by recombinant deoxyribonucleic acid (DNA) technology in a Chinese hamster ovary cell system, velaglucerase alfa by gene activation technology in a human cell line, and taliglucerase alpha by a novel plant cell-based protein expression system [16-19,31-33]. The purified enzyme imiglucerase is a monomeric glycoprotein composed of 497 amino acids. Recombinant enzyme differs from the native form and the therapeutic placental form (alglucerase) by a histidine for arginine amino acid substitution at position 495 . Oligosaccharide chains at the glycosylation sites are modified by sequential deglycosylation  to terminate in mannose moieties. Mannose groups may be recognized by endocytic receptors, facilitating uptake of the enzyme by the cell and trafficking to the lysosome. Velaglucerase differs from imiglucerase insomuch as the enzyme protein sequence is the native human sequence and greater mannose display is achieved. Kifunensine, a mannosidase I inhibitor, is used in the medium during production to obtain the desired glycosylation profile. The inhibition of the natural maturation of the glycans generates predominantly high mannose-type oligosaccharides . The taliglucerase platform uses genetically modified carrot cells. Terminal paucimannosidic type N-glycans are achieved by targeting to the plant storage vacuoles, where the terminal residues are normally removed .
Initiation — The initial dose is determined for the individual patient and depends upon age at presentation, the site(s) and extent of involvement, and the presence of irreversible pathology [6,24,37]. The usual starting dose for patients with GD1 is between 15 and 60 units/kg, administered intravenously over one to two hours every two weeks. The minimum recommended starting dose for children is 30 units/kg every two weeks [12,24]. The typical starting dose used for ERT in GD3 is 60 units/kg. In many areas of the world, ERT has been given safely in the home setting by home care nurses or patient self-infusion . One study has suggested that a shorter infusion time for velaglucerase may also be possible .
Large, prospective trials comparing dose regimens have not been performed. Initial doses of 30 to 60 int. units/kg for imiglucerase and taliglucerase and 60 int. units/kg for velaglucerase [16-19], given every two weeks, were safe and effective in improving visceral and bone marrow disease and quality of life in patients with GD1 [15,21,40-42]. Progression of skeletal disease leading to irreversible skeletal damage has occurred in some patients treated with lower doses despite improvement in other parameters . However, others have described the development of bone manifestation on high-dose ERT . In addition, results from a retrospective study of registry patients suggest a dose response in bone mineral density improvement .
Long-term outcomes of ERT with imiglucerase at two centers using low-dose (median dose 15 to 30 units/kg every four weeks) and high-dose (median dose 80 units/kg every four weeks) treatment protocols in adult patients were compared retrospectively . Improvement in hemoglobin, platelet count, and hepatosplenomegaly was not significantly different between cohorts. Patients at the center using high-dose ERT had more rapid improvement in plasma chitotriosidase (a marker of alternative-type macrophage activation that is overexpressed in Gaucher cells) and bone marrow involvement as measured by magnetic resonance imaging (MRI). (See "Gaucher disease: Initial assessment, monitoring, and prognosis", section on 'Laboratory evaluation' and "Gaucher disease: Initial assessment, monitoring, and prognosis", section on 'Routine monitoring'.)
Modifications — Dose adjustments are made on an individual basis. Generally, patients with GD1 do not require more than 60 int. units/kg every other week.
●Dose increases – Increases in dose may be necessary to achieve therapeutic goals or for relapse following dose reduction . The dose should be increased by 50 percent, for example, if bone crises continue . An increased dose may also be indicated if visceromegaly, anemia, thrombocytopenia, and biomarkers fail to improve after six months . However, an increased dose is unlikely to reverse certain types of pathology (eg, osteonecrosis and fibrosis of the liver, spleen, or lung). Additional evaluation may be necessary for patients who are unable to achieve their therapeutic goals after three to six months, and other causes or contributions to pathology should be considered. (See "Gaucher disease: Initial assessment, monitoring, and prognosis".)
●Dose reductions – Dose reductions should only be considered after all relevant therapeutic goals have been met . Dose reductions must be accompanied by reassessment of disease severity (table 1 and table 2 and table 3) to ensure the maintenance of therapeutic goals (table 4).
●Treatment interruptions – Treatment is continued throughout the patient's life. Prolonged treatment interruptions are not recommended, because there are several reports of disease progression if this occurs [48-54]. Patients in whom interruptions of therapy are unavoidable require close monitoring during the time of discontinuation . Major problems in the production and supply of imiglucerase in 2009 and 2010 led to a six-month shortage, resulting in interruption of treatment and dose reduction. While this six-month interruption in treatment was associated with an increase in fatigue, modest falls in platelet count, increases in biomarkers, and occasional episodes of irreversible bone events, many patients were able to tolerate this interruption without adverse effects [55-57].
Nonneuronopathic — Although there is limited direct and published evidence from head-to-head studies, the available evidence suggests that all the ERTs are approximately equivalent in efficacy [15-19,21,58]. Response to treatment varies from patient to patient, but analysis of long-term data demonstrate certain trends for ERT in patients with nonneuronopathic (GD1) disease [21,24,59-66]:
●Anemia – Hemoglobin concentrations typically increase to normal or near-normal levels within 6 to 12 months [59,63], with a sustained response throughout five years . In phase-III clinical trials of velaglucerase, the mean increase in hemoglobin concentration was 2.75 g/dL (26 percent) over 24 months, after which improvements were maintained or continued at a slower rate .
●Thrombocytopenia – Patients with intact spleens usually have the greatest response within two years and have slower improvement thereafter . These patients have a smaller response if baseline thrombocytopenia is severe. Approximately one-quarter of patients still have thrombocytopenia (platelet count <120 x 109/L), with severe-persistent thrombocytopenia (platelet count <60 x 109/L) seen in 2 percent of patients after four to five years of therapy . Predictors for persistent thrombocytopenia include very low baseline platelet count and increased baseline splenic volume. Platelet counts usually return to normal in 6 to 12 months in the rare splenectomized patients with thrombocytopenia due to marrow failure .
●Visceral disease – Reduction in spleen and liver volumes usually occurs within six months after initiation . Hepatomegaly and splenomegaly decrease by up to 60 percent, but spleen volume may remain more than five times normal in some patients . In a study of taliglucerase alfa for treatment-naïve adult patients with GD1, significant reductions were observed in spleen and liver volumes after the initial nine months. Further reductions were observed in an extension period up to 36 months.
●Skeletal disease – Skeletal improvement may not be evident until after two to three years of therapy [21,24,60]. Regular assessment of bone mineral density, marrow infiltration, and the axial skeleton are recommended. Magnetic resonance imaging (MRI) provides semiquantitative assessment of marrow infiltration and the degree of bone infarction. In adult patients, serial dual-energy x-ray absorptiometry (DXA) of the lumbar spine and left and right hips, with protocols to exclude focal disease, are recommended .
●Biomarkers – Biomarkers of macrophage activation (chitotriosidase or CCL-18) or substrate and its products (eg, glucosylsphingosine [lyso-Gb1]) may be used to monitor effects of therapy [69,70]. Since the initial level is variable and reflects overall disease burden, each patient should be monitored with respect to their own baseline. A decline over time with biomarkers is expected with Gaucher-specific interventions, and fluctuation in the level should raise the possibility of an intercurrent unrelated pathology, nonadherence to medication, or, in the case of ERT, neutralizing antibodies.
A systematic review of the utility of lyso-Gb1 as a disease biomarker concluded that it was a statistically reliable diagnostic and pharmacodynamic biomarker, with some evidence of its ability as a prognostic biomarker .In previously untreated adult GD1 patients who received over 24 months of velaglucerase, mean levels of chitotriosidase and CCL18 decreased by 80 percent. Measurement of the half-life for normalization of lyso-Gb1 may be a useful indicator of response to ERT. In a study of low-dose ERT (15 units/kg) the half-life for normalization of lyso-Gb1 was 14.8 months in 17 patients who received velaglucerase, while the corresponding decay half-life for spleen shrinkage was 118 months .
●Other – Reduction in fatigue is usually seen within six months of onset of therapy .
Treating children with ERT may mitigate or prevent the complications that occur later in life, particularly skeletal abnormalities [7,47,73-75]. Long-term ERT was associated with normalization or near normalization of height, hemoglobin level, platelet count, liver and spleen volume, and bone mineral density among 884 children registered in the Gaucher Registry . Early improvements were sustained with treatment continued for 20 years in another long-term follow-up study .
A systematic review and pooled analysis of observational studies of ERT (imiglucerase) in adults found that the lumbar spine fat fraction approximately doubled compared with baseline measurements . The percentage of responders to ERT based upon an increase in MRI T1-weighted signal and decrease in bone marrow infiltration ranged from 63 to 75 percent. The MRI bone marrow burden score also decreased after treatment (weighted mean difference [WMD] -4.98; 95% CI -8.38 to -1.57). However, there was not a significant increase in bone mineral density, as measured by lumbar spine and femur Z-scores, after ERT.
A small, open-label, phase-I/II study of velaglucerase showed similar results to historical imiglucerase data [16-19,78]. All five therapeutic goals (anemia, thrombocytopenia, hepatomegaly, splenomegaly, and skeletal pathology) were met in all patients (8 out of the original 12) who reached four years of treatment and were on a reduced dose for at least two years. The efficacy and safety of velaglucerase alfa compared with imiglucerase in adult and pediatric patients were demonstrated in a nine-month, global, randomized, noninferiority study comparing velaglucerase alfa with imiglucerase (60 int. units/kg every other week) in treatment-naïve patients aged 3 to 73 years with anemia and either thrombocytopenia or organomegaly .
Neuronopathic — Guidelines for the use of ERT in patients with neuronopathic GD are less well established. The recombinant enzyme does not cross the blood-brain barrier and therefore has limited ability to impact CNS disease. However, non-neuronopathic manifestations of GD respond to ERT [27,28]. In GD3, central neurologic disease was often stable, probably due to the general improved well-being of treated patients [79-82]. In a series of 21 patients ages 8 months to 35 years with GD3 who were treated with individually adjusted doses of enzyme and followed for two to eight years :
●Improvement occurred in hemoglobin levels, platelet count, and acid phosphatase values.
●Spleen and liver volume decreased, and bone structure improved.
●Asymptomatic interstitial lung disease, present in 19 patients, did not respond to treatment.
●Neurologic responses were variable:
•Supranuclear gaze palsy was unchanged in 19 patients, improved in 1, and worsened in 1.
•Auditory brainstem response (ABR) improved in 2 patients, was unchanged in 17, and deteriorated in 2. In another report, all eight children receiving high-dose ERT had deterioration in ABR .
In pregnancy — Published  and original data from several large treatment centers have been summarized in a comprehensive review of ERT for GD during pregnancy [85,86]. In some instances, pregnancy in GD may be complicated by deterioration in hematologic disease, organomegaly, and bone involvement. Previously undiagnosed GD can come to medical attention as a result. Data suggest a reduced risk of Gaucher-related complications in women treated with alglucerase and/or imiglucerase during delivery and the postpartum period [85-88]. There was no report of any untoward effects of alglucerase and/or imiglucerase on the fetus or on breastfed infants of treated mothers.
Adverse effects — ERT for GD is generally well tolerated [42,89]. The side effects are usually related to the intravenous infusion and include fever, chills, and flu-like symptoms . The mechanism is thought to be immune related but not immunoglobulin E (IgE) mediated. Acute IgE-mediated reactions are rare. When they occur, symptoms may include pruritus, flushing, urticaria/angioedema, chest discomfort, respiratory symptoms, cyanosis, and hypotension. ERT can be continued in most patients. In difficult cases, the infusion rate should be reduced and antihistamines and/or glucocorticoids given before the infusion .
Approximately 13 to 15 percent of treated patients develop anti-drug immunoglobulin G (IgG) antibody to the enzyme [23,89-91]. Many of these patients stop producing antibody after two to three years of therapy . The development of antibody is occasionally associated with diminished effectiveness of ERT and/or clinical deterioration [92,93]. However, such events are infrequent. In clinical trials of velaglucerase alfa, for example, 1 of 94 patients developed IgG-neutralizing antibodies to the enzyme. No infusion-related reactions were reported for this patient. No patients developed IgE antibodies to the enzyme. Reports of anti-drug antibodies to taliglucerase alfa range from 14 percent, in patients switched from imiglucerase, to 53 percent, in patients previously naïve to enzyme replacement .
Monitoring — Routine monitoring of disease activity should be carried out during ERT. Monitoring should be in accordance with at least the minimum recommendations for effective monitoring of patients provided by the International Collaborative Gaucher Group (ICGG) [10,95]. The recommended monitoring tests and schedule are discussed in detail separately (table 4). (See "Gaucher disease: Initial assessment, monitoring, and prognosis", section on 'Routine monitoring'.)
Patients who do not achieve their therapeutic goals should undergo evaluation for confounding factors (eg, poor compliance with therapy; development of comorbid conditions, such as malignancy or immune thrombocytopenia; or development of neutralizing antibody). The additional evaluation varies depending upon the goal that is not achieved.
Routine monitoring for the development IgG antibodies to the enzyme is not recommended, since it is an uncommon event. A pretreatment sample should routinely be drawn and stored. Subsequent samples should be drawn and tested (in parallel with the stored baseline sample) if clinically indicated, for example, if infusion reactions occur or if there is a suspicion of diminished efficacy of treatment. (See "Clinical features and diagnosis of pulmonary hypertension of unclear etiology in adults" and 'Adverse effects' above.)
SUBSTRATE REDUCTION THERAPY — Substrate reduction therapy (SRT), which reduces glycolipid accumulation by decreasing the synthesis of glucocerebroside, the substrate of the deficient enzyme, is an alternative to enzyme replacement therapy (ERT) for some adult patients [14,96-101]. Eliglustat is approved for a broader range of use than miglustat.
Eliglustat was approved in the United States in 2014 and the European Union in 2015 as a first-line treatment for adults with type 1 GD (GD1) [102,103]. Dosing of eliglustat is based upon patient cytochrome P450, subfamily IID, polypeptide 6 (CYP2D6) metabolizer status. The dose for extensive and intermediate metabolizers is 84 mg orally twice daily and for poor metabolizers is 84 mg once daily. Eliglustat is not indicated in patients who are CYP2D6 ultra-rapid metabolizers, since they may not achieve adequate concentrations of eliglustat to achieve a therapeutic effect. Concomitant use of CYP2D6 and CYP3A inhibitors is contraindicated. The most common strong and moderate inhibitors are listed in the tables (table 6 and table 7), but other drug interactions are possible. For specific interactions, use the Lexicomp drug interactions program included with UpToDate.
Eliglustat is not approved during pregnancy due to limited data. Pregnancy outcomes in patients who had unplanned pregnancies during eliglustat clinical trials have been described: In phase-II and III trials, 18 women had 19 pregnancies, resulting in 14 healthy infants from 13 pregnancies, 3 elective terminations, 1 ectopic pregnancy, 1 spontaneous abortion, and 1 in utero death .
Eliglustat is not advised in patients with galactose intolerance, lactase deficiency or glucose-galactose malabsorption, or cardiac disease including long QT syndrome or use of class IA or III antiarrhythmic drugs, and special care should be used in kidney or hepatic impairment .
Miglustat (N-butyldeoxynojirimycin), an earlier form of SRT, is approved in the United States for restricted use in adults with GD who are medically unable to receive ERT  and in Europe for symptomatic adult patients with mild-to-moderate disease in whom ERT is unsuitable (eg, venous access is problematic or the patient has a history of a severe infusion reaction) . Miglustat was also evaluated as a maintenance therapy for patients whose disease had stabilized during treatment with imiglucerase and was found to maintain clinical stability in some patients . The recommended dose of miglustat is 100 mg orally three times per day . Miglustat is contraindicated in pregnancy and in patients wishing to start a family due to the potential for causing birth defects and infertility .
In a randomized trial of 40 previously untreated adults with GD1 and baseline splenomegaly and thrombocytopenia, treatment with eliglustat (50 or 100 mg orally twice daily) for nine months lead to greater improvements in spleen and liver volume, platelet count, and hemoglobin level compared with placebo .
Adults with GD1 treated with ERT for at least three years who had stable disease were randomly assigned 2:1 to receive oral eliglustat (n = 106) twice daily or intravenous imiglucerase (n = 54) every other week for 12 months in a phase-III, open-label, noninferiority study . Eliglustat was noninferior to imiglucerase, with a between-group difference of -8.8 percent (95% CI -17.6 to 4.2) in the composite endpoint of decreased hematologic measurements (hemoglobin and platelet count) and increased organ volume (spleen and liver). These findings suggest that eliglustat can be used as first-line or maintenance therapy in adult patients with GD1.
Studies of miglustat have only shown modest improvements in mean liver and spleen volumes and slight changes in hemoglobin levels and platelet counts (increased in therapy-naïve patients and decreased in those who had previously received ERT) [96,109,113-115]. In addition, miglustat does not appear to have significant benefits on certain neurologic manifestations of type 3 GD (GD3) despite its ability to cross the blood-brain barrier. . The use of miglustat is therefore only indicated for adult GD1 patients with mild-to-moderate GD who cannot receive ERT.
Side effects of miglustat treatment include diarrhea (79 percent of patients in one study), weight loss, tremor, and peripheral neuropathy [96,113]. Patients treated with miglustat should be monitored for emergent neuropathy. Gastrointestinal side effects may also improve with dietary modifications and/or antidiarrheal medications . Patients on eliglustat should be monitored for possible drug interactions due to poor drug metabolism related to cytochrome P450 2D6 (CYP2D6) activity. For specific interactions, use the Lexicomp drug interactions program included with UpToDate.
A brain-penetrant SRT (venglustat) is in clinical trials for GD3 with a favorable safety profile in adults with GD3 (NCT02843035). This drug was also used in patients with glucosylceramidase beta 1 (GBA1) associated Parkinson disease (PD), but the study was halted when it did not meet efficacy parameters.
OTHER TREATMENT OPTIONS
Splenectomy — The availability of enzyme replacement therapy (ERT) has limited the indications for splenectomy. It is primarily performed if other measures fail to control life-threatening thrombocytopenia with high risk of bleeding. Other possible indications include unremitting abdominal pain caused by recurrent splenic infarction, severe restrictive pulmonary disease, inferior vena cava syndrome, or inability to receive ERT or substrate reduction therapy (SRT) . (See "Gaucher disease: Pathogenesis, clinical manifestations, and diagnosis", section on 'Visceral disease'.)
Before ERT was available, splenectomy was performed to improve thrombocytopenia and anemia. Partial splenectomy was sometimes performed to minimize the risk of overwhelming sepsis with total splenectomy. However, partial splenectomy had limited success and was associated with serious complications, including accelerated bone destruction, regrowth of the splenic remnant with recurrence of symptoms , and more rapid central nervous system (CNS) deterioration in patients with type 3a (Norrbottnian) disease . Total splenectomy was associated with a worse bone outcome than partial splenectomy in another series of patients . It is uncertain whether bony deterioration is a direct result of splenectomy, but one study has documented a strong temporal relationship between splenectomy and subsequent episodes of avascular necrosis .
Specific precautions must be taken to prevent sepsis in patients who require splenectomy. These are discussed separately. (See "Prevention of infection in patients with impaired splenic function".)
Hematopoietic cell transplantation — Hematopoietic cell transplantation (HCT) can provide a definitive cure for GD [121-124]. However, this procedure is associated with substantial morbidity and mortality and therefore has been effectively replaced by ERT and SRT in clinical practice [125,126]. HSCT is still considered in patients with type 3 GD (GD3) who present prior to the onset of neurologic signs or symptoms.
Gene therapy — Future treatment of GD may include gene therapy . In an animal model, gene therapy through retroviral transduction of bone marrow from mice with type 1 GD (GD1) both prevented the development of GD and corrected an established GD phenotype . In mice with established GD, gene therapy resulted in normalization of glucosylceramide concentrations and resolution of Gaucher cell infiltration of bone marrow, spleen, and liver five to six months after transplantation .
Two types of gene therapy vectors are under development as potential treatments for GD, one using adeno-associated vectors (AAVs), which are nonintegrating vectors, and one using lentiviruses, which do integrate. Both have been shown to mediate persistent transgene expression in cells.
A phase-I/II clinical trial using AAV9 gene therapy for young patients with neuronopathic GD (NCT04411654) aims to deliver a healthy copy of GBA1 into the cisterna magna as a one-time injection. After dosing, this therapy will be assessed for safety, tolerability, immunogenicity, biomarkers, and efficacy over a period of 12 months.
A second clinical trial is using a lentiviral-based gene therapy for GD1 (NCT04145037). Hematopoietic stem cells are harvested from the blood or bone marrow and genetically modified ex vivo with a lentivirus carrying wild-type GBA1 that, when successfully integrated into the human genome, expresses the corrected GCase enzyme.
A third study is using liver-targeted AAV gene therapy for GD1. Preclinical data suggest that a single injection of the AAV-based GBA1 construct may produce fully functioning GCase enzyme and prevent the accumulation of lipid substrates. In these laboratory-based animal studies, functioning GCase is found at long-term sustained steady-state levels within the bloodstream and is taken up by macrophages in key organs (NCT05324943).
Enzyme enhancement therapy — Enzyme enhancement therapy (EET), which attempts to increase the residual function of mutant enzymes, is another potential future therapy for GD . In EET, pharmacologic or chemical chaperones are used to stabilize folding of mutant glucocerebrosidase [129-132] or decrease its degradation . Chemical chaperones for the treatment of GD have been evaluated in clinical trials, but the development program of the lead compound GD (afegostat tartrate) was suspended as a result of lack of efficacy .
Ambroxol, a mucolytic agent that is not available in the United States but is used in other countries, has been proposed as a candidate pharmacologic chaperone. In an open-label pilot study, five patients with neuronopathic GD received high-dose oral ambroxol in combination with ERT. Patients on this combination therapy significantly increased lymphocyte glucocerebrosidase activity and decreased glucosylsphingosine levels in the cerebrospinal fluid. Myoclonus, seizures, and pupillary light reflex dysfunction improved in all patients. Relief from myoclonus led to recovery of gross motor function in two patients who subsequently regained walking ability . Data from an investigator-initiated registry found that 25 of 41 (61 percent) of patients treated with ambroxol (median duration 19 months, median dose 435 mg/day) reported improved or stable neurologic disease, reduced fatigue, and increased physical activity .
Another set of molecules, histone deacetylase inhibitors (HDACIs), have been studied as a potential class of medications to treat GD, as well as other protein misfolding diseases such as Niemann-Pick type C disease, Huntington disease, and cystic fibrosis. A known HDACI, suberoylanilide hydroxamic acid (SAHA), and a novel investigational HDACI reported in a 2011 study were found to increase GCase activity in fibroblasts from patients with GD1 and GD2 by modulating two molecular chaperones, heat-shock protein (HSP) 90 and HSP .
Another study tested arimoclomol, a small molecule that increases the levels of HSP70, a chaperone that helps to fold glucocerebrosidase. This HSP amplifier can cross the blood-brain barrier and was successfully used to enhance the folding, maturation activity, and localization of mutant GCase in patient cells and in a neuronal model of GD .
Other investigators have explored the possible utility of noninhibitory chaperones of GCase (NCGC) for the treatment of GD. A high-throughput screen for small-molecule chaperones of GCase, performed using a sample of patient spleen as the source of p.Asn409Ser mutant GCase, resulted in the identification of the first noninhibitory chaperones . A lead molecule increased GCase activity and reversed lipid storage in patient-derived induced pluripotent stem cell (iPSC) macrophages, restoring the impaired macrophage function . A second noninhibitory chaperone was reported to increase GCase activity and to reverse lipid storage in patient-derived iPSC-dopaminergic neurons . Another small-molecule modulator, S-181, was found to increase the activity of mutant and wild-type GCase in an iPSC-dopaminergic model carrying the c.84insG mutation, as well as in a murine model .
SUPPORTIVE CARE — Supportive care measures are necessary to manage bone disease, bleeding tendency, and other associated conditions (eg, parkinsonism). Management also includes addressing the psychosocial needs of the patient .
Skeletal disease — The treatment of bone disease is directed toward the prevention of irreversible complications, such as avascular necrosis .
●The possibility of osteomyelitis should be considered during episodes of bone pain since delayed diagnosis of osteomyelitis is associated with increased morbidity . Blood cultures, imaging studies (ie, radionuclide scan, magnetic resonance imaging [MRI]), and/or bone biopsies and cultures should be obtained as warranted. (See "Hematogenous osteomyelitis in children: Evaluation and diagnosis".)
●Bone pain crises can be ameliorated by intravenous fluids and analgesia. Options for analgesia include acetaminophen and nonsteroidal antiinflammatory agents . Narcotics may be necessary for severe crises but are not effective in all patients . Oral prednisolone (20 mg/m2 per day) may be helpful in such patients.
●Alendronate and other bisphosphonate drugs  are a potential adjunctive therapy for adult patients whose osteopenia is refractory to enzyme replacement therapy (ERT), although they do not address the underlying defect causing the bone disease. In a controlled trial, patients who were treated with alendronate for 18 months had increased lumbar bone mineral density compared with controls . Long-bone radiographs showed no change in focal lesions or bone deformities in either group. Skeletal health may be improved by common measures, including adequate calcium and vitamin D .
●Orthopedic procedures, such as hip replacement, may improve the quality of life. However, the success of these procedures is sometimes limited by the cortical thinning that frequently is present. Four patients at one center had successful total hip replacement with uncemented components at least one year after onset of ERT . The bone beyond the osteonecrotic areas was noted to have a normal appearance and consistency at the time of surgery in these patients. These procedures should be undertaken at centers experienced with surgical management of metabolic bone disease. Findings from one series suggest that use of ERT at any time improves outcomes for total hip replacements .
Bleeding tendency — Patients with GD have an increased risk of bleeding because of thrombocytopenia, defective platelet function, and/or coagulation factor abnormalities. They require appropriate evaluation and preparation before surgical procedures or pregnancy [6,23]. (See "Approach to the adult with a suspected bleeding disorder" and "Approach to the child with bleeding symptoms" and "Preoperative assessment of hemostasis" and "Overview of the etiology and evaluation of vaginal bleeding in pregnancy".)
Neuronopathic disease — Supportive care is necessary for the neurologic disease in patients with type 2 GD (GD2) or type 3 GD (GD3)  This is usually best delivered under the care of an experienced pediatric neurologist. However, as treated patients with GD3 are reaching adulthood, it is important to shift care to adult specialists. For GD2, a team approach including speech pathologists for swallow evaluations and a palliative care team can be helpful. (See "Seizures and epilepsy in children: Initial treatment and monitoring" and "Aspiration due to swallowing dysfunction in children" and "Symptomatic (secondary) myoclonus".)
Other complications — Patients with GD and clinical features of Parkinson disease (PD) are managed the same as other patients with PD. In the future, therapies may be designed to specifically target GBA1-associated PD. (See "Nonpharmacologic management of Parkinson disease" and "Initial pharmacologic treatment of Parkinson disease".)
Similarly, patients with hematologic malignancies are normally referred to an oncologist or hematologist. (See appropriate topic reviews on lymphoma, leukemia, and multiple myeloma.)
Patients with severe liver disease and hepatopulmonary syndrome may require liver transplantation [148,149]. (See "Hepatopulmonary syndrome in adults: Prevalence, causes, clinical manifestations, and diagnosis" and "Liver transplantation in adults: Patient selection and pretransplantation evaluation".)
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Gaucher disease".)
SUMMARY AND RECOMMENDATIONS
●Treatment goals – The basic goals of treatment of Gaucher disease (GD) are elimination of symptoms, prevention of irreversible complications, and improvement in the overall health and quality of life. An additional goal in children is optimization of growth and development. Treatment of GD is tailored to the individual patient because of the variability in the manifestations, severity, and progression of the disease. An international panel of clinicians with extensive clinical experience in GD has developed a list of therapeutic goals to be used as guides for optimal individualized treatment (table 1 and table 2 and table 3). (See 'Therapeutic goals' above.)
●Enzyme replacement therapy (ERT) and substrate reduction therapy (SRT) for nonneuronopathic (type 1) GD (GD1) – The decision to offer ERT or SRT in nonneuronopathic GD (GD1) is based upon age and disease severity, as determined by the initial assessment, or significant disease progression, as demonstrated through regular follow-up (table 4). (See 'Indications' above and 'Nonneuronopathic' above.)
•All symptomatic children and adult with severe disease – We recommend ERT with recombinant glucocerebrosidases (imiglucerase, velaglucerase alfa, or taliglucerase) for all symptomatic children and for adults with severe manifestations of nonneuronopathic GD (GD1) (Grade 1B). SRT with eliglustat is a suitable alternative for adults with severe symptomatic disease and suitable metabolizer status. (See 'Enzyme replacement therapy' above and 'Substrate reduction therapy' above.)
•Other adult patients – Treatment options for adult patients with GD1 without severe manifestations include SRT with eliglustat or ERT. The choice is largely based upon patient preference. Dosing of eliglustat is determined by metabolizer status. A small number of adult patients who metabolize eliglustat more quickly or at an undetermined rate are not eligible for treatment with this drug. SRT with miglustat, an inhibitor of glucosylceramide synthase, is an option in adult patients with mild-to-moderate GD1 who are unwilling or unable to receive ERT. The recommended dose of miglustat is 100 mg orally three times per day. Patients treated with miglustat should be monitored for emergent neuropathy. (See 'Substrate reduction therapy' above and 'Enzyme replacement therapy' above.)
●ERT for neuronopathic GD:
•Type 3 GD (GD3) – We suggest ERT for patients with neuronopathic GD3 and severe visceral symptoms (Grade 2B). In addition, we suggest ERT in patients with a genotype predictive of GD3 or with a family history of GD3 who are identified early in the disease course, before the onset of neurologic signs or symptoms (Grade 2C).
•Type 2 GD (GD2) – We suggest not administering ERT in patients with neuronopathic GD3 (Grade 2C). ERT may have palliative effects on visceral manifestations in patients with GD2, but it does not alter the fatal neurologic outcome. (See 'Indications' above and 'Neuronopathic' above.)
●ERT initial dosing – ERT is individualized. Factors considered in choosing the initial dose include age at presentation, comorbid conditions, the site(s) and extent of involvement, and the presence of irreversible pathology. For most patients, we use an initial dose of 30 to 60 int. units/kg intravenously every two weeks, although some centers begin with 15 int. units/kg, increasing the dose if needed. The minimum recommended starting dose for children is 30 int. units/kg. (See 'Administration' above.)
●Timing of treatment response to ERT – Treatment response varies, but, in general, improvements occur within six months after initiation of therapy and include reduction of spleen and liver volumes, resolution of thrombocytopenia and anemia, and reduction in fatigue. Improvement in skeletal disease may not be evident for two to three years. (See 'Effectiveness' above.)
●Monitoring and dose adjustment for ERT – Routine monitoring of disease activity is performed during ERT (table 4). Dose adjustments are made on an individual basis. We advise increasing the dose if visceromegaly, anemia, thrombocytopenia, and biomarkers fail to improve after six months or if the patient fails to achieve specific therapeutic goals. We advise increasing the dose by 50 percent if bone crises continue. We suggest that dose reductions be considered only after all relevant therapeutic goals have been met. Dose reductions must be accompanied by reassessment of disease severity to ensure the maintenance of therapeutic goals. Treatment is continued throughout the patient's life. Treatment interruptions are usually not recommended. (See 'Administration' above and "Gaucher disease: Initial assessment, monitoring, and prognosis".)
●Other treatment options – The availability and efficacy of ERT have limited the indications for splenectomy and hematopoietic cell transplantation (HCT). Splenectomy is indicated if other measures fail to control life-threatening thrombocytopenia. Bone marrow transplantation may be an option in patients known to be at-risk for neuronopathic disease who present early in the disease course. (See 'Other treatment options' above.)
●Supportive care – Supportive care measures are necessary to manage bone disease, bleeding tendency, and other associated conditions (eg, parkinsonism). Management also includes addressing the psychosocial needs of the patient. (See 'Supportive care' above.)
ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Patrick Deegan, MD, MRCPI, FRCP, who contributed to earlier versions of this topic review.